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Hippocampus

Brain: Hippocampus

The hippocampus is located in the medial temporal lobe of the brain. In this lateral view of the human brain, the frontal lobe is at left,the occipital lobe at right, and the temporal and parietal lobes have largely been removed to reveal the hippocampus underneath.

NeuroNames hier-164 [1]

MeSH Hippocampus [2]

NeuroLex ID birnlex_721 [3]

The hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbicsystem and plays important roles in long-term memory and spatial navigation. Like the cerebral cortex, with which itis closely associated, it is a paired structure, with mirror-image halves in the left and right sides of the brain. Inhumans and other primates, the hippocampus is located inside the medial temporal lobe, beneath the cortical surface.It contains two main interlocking parts: Ammon's horn and the dentate gyrus.In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problemsand disorientation appear among the first symptoms. Damage to the hippocampus can also result from oxygenstarvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampaldamage may experience anterograde amnesia—the inability to form or retain new memories.In rodents, the hippocampus has been studied extensively as part of a brain system responsible for behavioralinhibition and attention, spatial memory, and navigation. A major symptom of hippocampal damage in rats isincreased activity. Many neurons in the rat and mouse hippocampus respond as place cells: that is, they fire bursts ofaction potentials when the animal passes through a specific part of its environment. Hippocampal place cells interactextensively with head direction cells, whose activity acts as an inertial compass, and with grid cells in theneighboring entorhinal cortex.Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used asa model system for studying neurophysiology. The form of neural plasticity known as long-term potentiation (LTP)was first discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believedto be one of the main neural mechanisms by which memory is stored in the brain.

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Name

The Hungarian neuroscientist László Seress' 1980preparation of the human hippocampus and fornix

compared with a seahorse.

The earliest description of the ridge running along the floor of thetemporal horn of the lateral ventricle comes from the Venetiananatomist Julius Caesar Aranzi (1587), who initially likened it to aseahorse, using the Latin: hippocampus (from Greek: ἵππος, "horse"and Greek: κάμπος, "sea monster") or alternatively to a silkworm. TheGerman anatomist Duvernoy (1729), the first to illustrate the structure,also wavered between "seahorse" and "silkworm." "Ram's horn" wasproposed by the Danish anatomist Jacob Winsløw in 1732; and adecade later his fellow Parisian, the surgeon de Garengeot, used "cornuAmmonis" - horn of (the ancient Egyptian god) Amun.[4]

Another mythological reference appeared with the term pes hippocampi, which may date back to Diemerbroeck in1672, introducing a comparison with the shape of the folded back forelimbs and webbed feet of the Classicalhippocampus (Greek: ἱππόκαμπος), a sea monster with a horse's forequarters and a fish's tail. The hippocampus wasthen described as pes hippocampi major, with an adjacent bulge in the occipital horn, the calcar avis, being namedpes hippocampi minor.[4] The renaming of the hippocampus as hippocampus major, and the calcar avis ashippocampus minor, has been attributed to Félix Vicq-d'Azyr systematising nomenclature of parts of the brain in1786. Mayer mistakenly used the term hippopotamus in 1779, and was followed by some other authors until KarlFriedrich Burdach resolved this error in 1829. In 1861 the hippocampus minor became the centre of a dispute overhuman evolution between Thomas Henry Huxley and Richard Owen, satirised as the Great Hippocampus Question.The term hippocampus minor fell from use in anatomy textbooks, and was officially removed in the NominaAnatomica of 1895.[5]

Today, the structure is called the hippocampus rather than hippocampus major, with pes hippocampi often beingregarded as synonymous with De Garengeot's "cornu Ammonis",[4] a term which survives in the names of the fourmain histological divisions of the hippocampus: CA1, CA2, CA3 and CA4.[6]

FunctionsHistorically, the earliest widely held hypothesis was that the hippocampus is involved in olfaction. This idea was castinto doubt by a series of anatomical studies that did not find any direct projections to the hippocampus from theolfactory bulb.[7] However, later work did confirm that the olfactory bulb does project into the ventral part of thelateral entorhinal cortex, and field CA1 in the ventral hippocampus sends axons to the main olfactory bulb[8] , theanterior olfactory nucleus, and to the primary olfactory cortex. There continues to be some interest in hippocampalolfactory responses, particularly the role of the hippocampus in memory for odors, but few people believe today thatolfaction is its primary function.[9] [10]

Over the years, three main ideas of hippocampal function have dominated the literature: inhibition, memory, andspace. The behavioral inhibition theory (caricatured by O'Keefe and Nadel as "slam on the brakes!")[11] was verypopular up to the 1960s. It derived much of its justification from two observations: first, that animals withhippocampal damage tend to be hyperactive; second, that animals with hippocampal damage often have difficultylearning to inhibit responses that they have previously been taught, especially if the response requires remainingquiet as in a passive avoidance test. Jeffrey Gray developed this line of thought into a full-fledged theory of the roleof the hippocampus in anxiety.[12] The inhibition theory is currently the least popular of the three.[13]

The second major line of thought relates the hippocampus to memory. Although it had historical precursors, this idea derived its main impetus from a famous report by Scoville and Brenda Milner[14] describing the results of surgical destruction of the hippocampus (in an attempt to relieve epileptic seizures), in a patient named Henry Gustav

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Molaison,[15] known until his death in 2008 as H.M. The unexpected outcome of the surgery was severe anterogradeand partial retrograde amnesia: H.M. was unable to form new episodic memories after his surgery and could notremember any events that occurred just before his surgery, but retained memories for things that happened yearsearlier, such as his childhood. This case produced such enormous interest that H.M. reportedly became the mostintensively studied medical subject in history.[16] In the ensuing years, other patients with similar levels ofhippocampal damage and amnesia (caused by accident or disease) have been studied as well, and thousands ofexperiments have studied the physiology of activity-driven changes in synaptic connections in the hippocampus.There is now almost universal agreement that the hippocampus plays some sort of important role in memory;however, the precise nature of this role remains widely debated.[17] [18]

The third important theory of hippocampal function relates the hippocampus to space. The spatial theory wasoriginally championed by O'Keefe and Nadel, who were influenced by E.C. Tolman's theories about "cognitivemaps" in humans and animals. O'Keefe and his student Dostrovsky in 1971 discovered neurons in the rathippocampus that appeared to them to show activity related to the rat's location within its environment.[19] Despiteskepticism from other investigators, O'Keefe and his co-workers, especially Lynn Nadel, continued to investigatethis question, in a line of work that eventually led to their very influential 1978 book The Hippocampus as aCognitive Map.[20] As with the memory theory, there is now almost universal agreement that spatial coding plays animportant role in hippocampal function, but the details are widely debated.[21]

Role in memoryPsychologists and neuroscientists generally agree that the hippocampus has an important role in the formation ofnew memories about experienced events (episodic or autobiographical memory).[18] [22] Part of this role ishippocampal involvement in the detection of novel events, places and stimuli.[23] Some researchers view thehippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory(memories that can be explicitly verbalized—these would include, for example, memory for facts in addition toepisodic memory).[17]

Due to bilateral symmetry the brain has a hippocampus in both cerebral hemispheres, so every normal brain has twoof them. If damage to the hippocampus occurs in only one hemisphere, leaving the structure intact in the otherhemisphere, the brain can retain near-normal memory functioning.[24] Severe damage to the hippocampus in bothhemispheres results in profound difficulties in forming new memories (anterograde amnesia), and often also affectsmemories formed before the damage (retrograde amnesia). Although the retrograde effect normally extends someyears before the brain damage, in some cases older memories remain—this sparing of older memories leads to theidea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of thebrain.[25]

Damage to the hippocampus does not affect some types of memory, such as the ability to learn new motor orcognitive skills (playing a musical instrument, or solving certain types of puzzles, for example). This fact suggeststhat such abilities depend on different types of memory (procedural memory) and different brain regions.Furthermore, amnesic patients frequently show "implicit" memory for experiences even in the absence of consciousknowledge. For example, a patient asked to guess which of two faces they have seen most recently may give thecorrect answer the majority of the time, in spite of stating that they have never seen either of the faces before. Someresearchers distinguish between conscious recollection, which depends on the hippocampus, and familiarity, whichdepends on portions of the medial temporal cortex.[26]

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Role in spatial memory and navigation

Spatial firing patterns of seven place cellsrecorded from a single electrode in the dorsal

CA1 layer of a rat. The rat ran several hundredlaps clockwise around an elevated triangular

track, stopping in the middle of each arm to eat asmall portion of food reward. Black dots indicatepositions of the rat's head; colored dots indicateplaces where action potentials occurred, using a

different color for each cell.[27]

Studies conducted on freely moving rats and mice have shown thatmany hippocampal neurons have "place fields", that is, they fire burstsof action potentials when a rat passes through a particular part of theenvironment. Evidence for place cells in primates is limited, perhaps inpart because it is difficult to record brain activity from freely movingmonkeys. Place-related hippocampal neural activity has been reportedin monkeys moving around inside a room while seated in a restraintchair;[28] on the other hand, Edmund Rolls and his colleagues insteaddescribed hippocampal cells that fire in relation to the place a monkeyis looking at, rather than the place its body is located.[29] In humans,cells with location-specific firing patterns have been reported in astudy of patients with drug-resistant epilepsy who were undergoing aninvasive procedure to localize the source of their seizures, with a viewto surgical resection. The patients had diagnostic electrodes implantedin their hippocampus and then used a computer to move around in avirtual reality town.[30]

Place responses in rats and mice have been studied in hundreds ofexperiments over four decades, yielding a large quantity ofinformation.[21] Place cell responses are shown by pyramidal cells inthe hippocampus proper, and granule cells in the dentate gyrus. These constitute the great majority of neurons in thedensely packed hippocampal layers. Inhibitory interneurons, which make up most of the remaining cell population,frequently show significant place-related variations in firing rate, but much weaker than that shown by pyramidal orgranule cells. There is little if any spatial topography in the representation: cells lying next to each other in thehippocampus generally have uncorrelated spatial firing patterns. Place cells are typically almost silent when a rat ismoving around outside the place field, but reach sustained rates as high as 40 Hz when the rat is near the center.Neural activity sampled from 30–40 randomly chosen place cells carries enough information to allow a rat's locationto be reconstructed with high confidence. The size of place fields varies in a gradient along the length of thehippocampus, with cells at the dorsal end showing the smallest fields, cells near the center showing larger fields, andcells at the ventral tip fields that cover the entire environment.[21] In some cases, the firing rate of rat hippocampalcells depends not only on place but also on the direction a rat is moving, the destination toward which it is traveling,or other task-related variables.[31]

The discovery of place cells in the 1970s led to a theory that the hippocampus might act as a cognitive map—aneural representation of the layout of the environment.[32] Several lines of evidence support the hypothesis. It is afrequent observation that without a fully functional hippocampus, humans may not remember where they have beenand how to get where they are going: getting lost is one of the most common symptoms of amnesia.[33] Studies withanimals have shown that an intact hippocampus is required for some spatial memory tasks, particularly ones thatrequire finding the way to a hidden goal.[34] The "cognitive map hypothesis" has been further advanced by recentdiscoveries of head direction cells, grid cells, and border cells in several parts of the rodent brain that are stronglyconnected to the hippocampus.[21] [35]

Brain imaging shows that people have more active hippocampi when correctly navigating, as tested in a computer-simulated "virtual" navigation task.[36] Also, there is evidence that the hippocampus plays a role in finding shortcuts and new routes between familiar places. For example, London's taxi drivers must learn a large number of places and the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs). A study at University College London by Maguire, et al.. (2000)[37] showed that

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part of the hippocampus is larger in taxi drivers than in the general public, and that more experienced drivers havebigger hippocampi. Whether having a bigger hippocampus helps an individual to become a cab driver, or if findingshortcuts for a living makes an individual's hippocampus grow is yet to be elucidated. However, in that studyMaguire, et al.. examined the correlation between size of the grey matter and length of time that had been spent as ataxi driver, and found a positive correlation between the length of time an individual had spent as a taxi driver andthe volume of the right hippocampus. It was found that the total volume of the hippocampus remained constant, fromthe control group vs. taxi drivers. That is to say that the posterior portion of a taxi driver's hippocampus is indeedincreased, but at the expense of the anterior portion. There have been no known detrimental effects reported fromthis disparity in hippocampal proportions.[37]

Anatomy

Nissl-stained coronal section of the brain of a macaque monkey,showing hippocampus (circled). Source: brainmaps.org

Anatomically, the hippocampus is an elaboration of theedge of the cerebral cortex.[38] The structures that linethe edge of the cortex make up the so-called limbicsystem (Latin limbus = border): these include thehippocampus, cingulate cortex, olfactory cortex, andamygdala. Paul MacLean once suggested, as part of histriune brain theory, that the limbic structures comprisethe neural basis of emotion. Some neuroscientists nolonger believe that the concept of a unified "limbicsystem" is valid, though.[39] However, the hippocampusis anatomically connected to parts of the brain that areinvolved with emotional behavior--the septum, thehypothalamic mammillary body, and the anteriornuclear complex in the thalamus so its role as a limbicstructure cannot be completely dismissed.

The hippocampus as a whole has the shape of a curved tube, which has been analogized variously to a seahorse, aram's horn (Cornu Ammonis, hence the subdivisions CA1 through CA4), or a banana.[38] It can be distinguished as azone where the cortex narrows into a single layer of densely packed pyramidal neurons 3-6 cells deep in rats, whichcurl into a tight U shape; one edge of the "U," field CA4, is embedded into a backward facing strongly flexedV-shaped cortex, the dentate gyrus. It consists of ventral and dorsal portions, both of which share similarcomposition but are parts of different neural circuits.[40] This general layout holds across the full range ofmammalian species, from hedgehog to human, although the details vary. In the rat, the two hippocampi resemble apair of bananas, joined at the stems by the hippocampal commissure that crosses the midline under the anteriorcorpus callosum. In human or monkey brains, the portion of the hippocampus down at the bottom, near the base ofthe temporal lobe, is much broader than the part at the top. One of the consequences of this complex geometry is thatcross-sections through the hippocampus can show a variety of shapes, depending on the angle and location of thecut.

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Basic circuit of the hippocampus, as drawn by Santiago Ramon y Cajal. DG:dentate gyrus. Sub: subiculum. EC: entorhinal cortex

The entorhinal cortex (EC), located in theparahippocampal gyrus, is considered to bepart of the hippocampal region because ofits anatomical connections. The EC isstrongly and reciprocally connected withmany other parts of the cerebral cortex. Inaddition, the medial septal nucleus, theanterior nuclear complex and nucleusreuniens of the thalamus and thesupramammillary nucleus of thehypothalamus, as well as the raphe nucleiand locus coeruleus in the brainstem sendaxons to the EC. The main output pathway

(perforant path, first described by Ramon y Cajal) of EC axons comes from the large stellate pyramidal cells in layerII that "perforate" the subiculum and project densely to the granule cells in the dentate gyrus, apical dendrites of CA3get a less dense projection, and the apical dendrites of CA1 get a sparse projection. Thus, the perforant pathestablishes the EC as the main "interface" between the hippocampus and other parts of the cerebral cortex. Thedentate granule cell axons (called mossy fibers) pass on the information from the EC on thorny spines that exit fromthe proximal apical dendrite of CA3 pyramidal cells. Then, CA3 axons exit from the deep part of the cell body, andloop up into the region where the apical dendrites are located, then extend all the way back into the deep layers of theentorhinal cortex--the Shaffer collaterals completing the reciprocal circuit; field CA1 also sends axons back to theEC, but these are more sparse than the CA3 projection. Within the hippocampus, the flow of information from theEC is largely unidirectional, with signals propagating through a series of tightly packed cell layers, first to thedentate gyrus, then to the CA3 layer, then to the CA1 layer, then to the subiculum, then out of the hippocampus tothe EC, mainly due to collateralization of the CA3 axons. Each of these layers also contains complex intrinsiccircuitry and extensive longitudinal connections.[38]

Several other connections play important roles in hippocampal function.[38] Beyond the output to the EC, additionaloutput pathways go to other cortical areas including the prefrontal cortex. A very important large output goes to thelateral septal area and to the mammillary body of the hypothalamus. The hippocampus receives modulatory inputfrom the serotonin, norepinephrine, and dopamine systems, and from nucleus reuniens of the thalamus to field CA1.A very important projection comes from the medial septal area, which sends cholinergic and GABAergic fibers to allparts of the hippocampus. The inputs from the septal area play a key role in controlling the physiological state of thehippocampus: destruction of the septal area abolishes the hippocampal theta rhythm, and severely impairs certaintypes of memory.[41]

The cortical region adjacent to the hippocampus is known collectively as the parahippocampal gyrus (orparahippocampus).[42] It includes the EC and also the perirhinal cortex, which derives its name from the fact that itlies next to the rhinal sulcus. The perirhinal cortex plays an important role in visual recognition of complex objects,but there is also substantial evidence that it makes a contribution to memory which can be distinguished from thecontribution of the hippocampus, and that complete amnesia occurs only when both the hippocampus and theparahippocampus are damaged.[42]

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Physiology

Examples of rat hippocampal EEG and CA1 neural activity in the theta(awake/behaving) and LIA (slow-wave sleep) modes. Each plot show 20 seconds

of data, with a hippocampal EEG trace at the top, spike rasters from 40simultaneously recorded CA1 pyramidal cells in the middle (each raster line

represents a different cell), and a plot of running speed at the bottom. The top plotrepresents a time period during which the rat was actively searching for scattered

food pellets. For the bottom plot, the rat was asleep.

The hippocampus shows two major "modes"of activity, each associated with a distinctpattern of neural population activity andwaves of electrical activity as measured byan electroencephalogram (EEG). Thesemodes are named after the EEG patternsassociated with them: theta and largeirregular activity (LIA). The maincharacteristics described below are for therat, which is the animal most extensivelystudied.[43]

The theta mode appears during states ofactive, alert behavior (especiallylocomotion), and also during REM(dreaming) sleep.[44] In the theta mode, theEEG is dominated by large regular waveswith a frequency range of 6–9 Hz, and themain groups of hippocampal neurons(pyramidal cells and granule cells) showsparse population activity, which means thatin any short time interval, the great majorityof cells are silent, while the small remainingfraction fire at relatively high rates, up to 50spikes in one second for the most active ofthem. An active cell typically stays activefor half a second to a few seconds. As the rat behaves, the active cells fall silent and new cells become active, but theoverall percentage of active cells remains more or less constant. In many situations, cell activity is determinedlargely by the spatial location of the animal, but other behavioral variables also clearly influence it.

The LIA mode appears during slow-wave (non-dreaming) sleep, and also during states of waking immobility, suchas resting or eating.[44] In the LIA mode, the EEG is dominated by sharp waves, which are randomly timed largedeflections of the EEG signal lasting for 200–300 ms. These sharp waves also determine the population neuralactivity patterns. Between them, pyramidal cells and granule cells are very quiet (but not silent). During a sharpwave, as many as 5–10% of the neural population may emit action potentials during a period of 50 ms; many ofthese cells emit bursts of several action potentials.These two hippocampal activity modes can be seen in primates as well as rats, with the exception that it has beendifficult to see robust theta rhythmicity in the primate hippocampus. There are, however, qualitatively similar sharpwaves, and similar state-dependent changes in neural population activity.[45]

Theta rhythmBecause of its densely packed neural layers, the hippocampus generates some of the largest EEG signals of any brain structure. In some situations the EEG is dominated by regular waves at 3–10 Hz, often continuing for many seconds. These reflect subthreshold membrane potentials and strongly modulate the spiking of hippocampal neurons and synchronise across the hippocampus in a travelling wave pattern.[46] This EEG pattern is known as a theta rhythm.[47] Theta rhythmicity is very obvious in rabbits and rodents, and also clearly present in cats and dogs.

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Whether theta can be seen in primates is a vexing question.[48] In rats (the animals that have been the mostextensively studied), theta is seen mainly in two conditions: first, when an animal is walking or in some other wayactively interacting with its surroundings; second, during REM sleep.[49] The function of theta has not yet beenconvincingly explained, although numerous theories have been proposed.[43] The most popular hypothesis has beento relate it to learning and memory. For example, the phase with which theta at the time of stimulation of a neuronshapes the effect of that stimulation upon its synapses and therefore may affect learning and memory dependent uponsynaptic plasticity.[50] It is well-established that lesions of the medial septum—the central node of the thetasystem—cause severe disruptions of memory. However, the medium septum is more than just the controller of theta,it is also the main source of cholinergic projections to the hippocampus.[38] It has not been established that septallesions exert their effects specifically by eliminating the theta rhythm.[51]

Sharp wavesDuring sleep, or during waking states when an animal is resting or otherwise not engaged with its surroundings, thehippocampal EEG shows a pattern of irregular slow waves, somewhat larger in amplitude than theta waves. Thispattern is occasionally interrupted by large surges called sharp waves.[52] These events are associated with bursts ofspike activity, lasting 50–100 msec, in pyramidal cells of CA3 and CA1. They are also associated with short-lastinghigh-frequency EEG oscillations called "ripples", with frequencies in the range 150–200 Hz in rats. Sharp waves aremost frequent during sleep, when they occur at an average rate around 1 per second (in rats), but in a very irregulartemporal pattern. Sharp waves are less frequent during inactive waking states, and are usually smaller. Sharp waveshave also been observed in humans and monkeys. In macaques, sharp waves are robust, but do not occur asfrequently as in rats.[45]

One of the most interesting aspects of sharp waves is that they appear to be associated with memory. Wilson andMcNaughton 1994,[53] and numerous later studies, reported that when hippocampal place cells have overlappingspatial firing fields (and therefore often fire in near-simultaneity), they tend to show correlated activity during sleepfollowing the behavioral session. This enhancement of correlation, commonly known as reactivation, has been foundto occur mainly during sharp waves.[54] It has been proposed that sharp waves are, in fact, reactivations of neuralactivity patterns that were memorized during behavior, driven by strengthening of synaptic connections within thehippocampus.[55] This idea forms a key component of the "two-stage memory" theory, advocated by Buzsáki andothers, which proposes that memories are stored within the hippocampus during behavior, and then later transferredto the neocortex during sleep: sharp waves are suggested to drive Hebbian synaptic changes in the neocortical targetsof hippocampal output pathways.[56]

Long-term potentiationSince at least the time of Ramon y Cajal, psychologists have speculated that the brain stores memory by altering thestrength of connections between neurons that are simultaneously active.[57] This idea was formalized by DonaldHebb in 1948,[58] but for many years thereafter, attempts to find a brain mechanism for such changes came upempty. In 1973, Tim Bliss and Terje Lømo described a phenomenon in the rabbit hippocampus that appeared to meetHebb's specifications: a change in synaptic responsiveness induced by brief strong activation and lasting for hours,days, or longer.[59] This phenomenon was soon referred to as long-term potentiation, abbreviated LTP. As acandidate mechanism for memory, LTP has been studied intensively over the following years, and a great deal hasbeen learned about it.The hippocampus is a particularly favorable site for studying LTP because of its densely packed and sharply defined layers of neurons, but similar types of activity-dependent synaptic change have now been observed in many other brain areas.[60] The best-studied form of LTP occurs at synapses that terminate on dendritic spines and use the transmitter glutamate. Several of the major pathways within the hippocampus fit this description, and show LTP.[61]

The synaptic changes depend on a special type of glutamate receptor, the NMDA receptor, which has the special

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property of allowing calcium to enter the postsynaptic spine only when presynaptic activation and postsynapticdepolarization occur at the same time.[62] Drugs that interfere with NMDA receptors block LTP and also have majoreffects on some types of memory, especially spatial memory. Transgenic mice, genetically modified in ways thatdisable the LTP mechanism, also generally show severe memory deficits.[62]

Pathology

AgingAge-related conditions such as Alzheimer's disease (for which hippocampal disruption is one of the earliest signs[63]

) have a severe impact on many types of cognition, but even normal, healthy aging is associated with a gradualdecline in some types of memory, including episodic memory and working memory. Because the hippocampus isthought to play a central role in memory, there has been considerable interest in the possibility that age-relateddeclines could be caused by hippocampal deterioration.[64] Some early studies reported substantial loss of neurons inthe hippocampus of elderly people, but later studies using more precise techniques found only minimaldifferences.[64] Similarly, some MRI studies have reported shrinkage of the hippocampus in elderly people, but otherstudies have failed to reproduce this finding. There is, however, a reliable relationship between the size of thehippocampus and memory performance—meaning that not all elderly people show hippocampal shrinkage, but thosewho do tend to perform less well on some memory tasks.[65] There are also reports that memory tasks tend toproduce less hippocampal activation in elderly than in young subjects.[65] Furthermore, a randomized-control studypublished in 2011 found that aerobic exercise could increase the size of the hippocampus in adults aged 55 to 80 andalso improve spatial memory. [66]

In rats, where detailed studies of cellular physiology are possible, aging does not cause substantial cell loss in thehippocampus, but it alters synaptic connectivity in several ways.[67] Functional synapses are lost in the dentate gyrusand CA1 region, and NMDA receptor-mediated responses are reduced. These changes may account for deficits ininduction and maintenance of long-term potentiation, a form of synaptic plasticity that has been implicated inmemory. There are also age-related declines in hippocampal expression of several genes associated with synapticplasticity.[68] Finally, there are differences in the stability of "place cell" representations. In young rats, thearrangement of place fields is usually altered if the rat is moved into a different environment, but remains the same ifa rat is returned to an environment it has visited previously. In aged rats, the place fields frequently fail to "remap"when a rat is moved to a different environment, and also frequently fail to restore the original "map" when the rat isreturned to the same environment.

StressThe hippocampus contains high levels of glucocorticoid receptors, which make it more vulnerable to long-termstress than most other brain areas.[69] Stress-related steroids affect the hippocampus in at least three ways: first, byreducing the excitability of some hippocampal neurons; second, by inhibiting the genesis of new neurons in thedentate gyrus; third, by causing atrophy of dendrites in pyramidal cells of the CA3 region. There is evidence thathumans who have experienced severe, long-lasting traumatic stress, show atrophy of the hippocampus, more than ofother parts of the brain.[70] . These effects show up in post-traumatic stress disorder, and they may contribute to thehippocampal atrophy reported in schizophrenia and severe depression. A recent study has also revealed atrophy as aresult of depression, but this can be stopped with anti-depressants, even if they are not effective in relieving othersymptoms.[71] Hippocampal atrophy is also frequently seen in Cushing's syndrome, a disorder caused by high levelsof cortisol in the bloodstream. At least some of these effects appear to be reversible if the stress is discontinued.There is, however, evidence mainly derived from studies using rats that stress shortly after birth can affecthippocampal function in ways that persist throughout life.[72]

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EpilepsyThe hippocampus is often the focus of epileptic seizures: hippocampal sclerosis is the most commonly visible type oftissue damage in temporal lobe epilepsy.[73] It is not yet clear, though, whether the epilepsy is usually caused byhippocampal abnormalities, or the hippocampus is damaged by cumulative effects of seizures.[74] In experimentalsettings where repetitive seizures are artificially induced in animals, hippocampal damage is a frequent result: thismay be a consequence of the hippocampus being one of the most electrically excitable parts of the brain. It may alsohave something to do with the fact that the hippocampus is one of very few brain regions where new neuronscontinue to be created throughout life.[75]

SchizophreniaThe causes of schizophrenia are not at all well understood, but numerous abnormalities of brain structure have beenreported. The most thoroughly investigated alterations involve the cerebral cortex, but effects on the hippocampushave also been described. Many reports have found reductions in the size of the hippocampus in schizophrenicsubjects.[76] The changes probably result from altered development rather than tissue damage, and show up even insubjects who have never been medicated. Several lines of evidence implicate changes in synaptic organization andconnectivity.[76] It is unclear whether hippocampal alterations play any role in causing the psychotic symptoms thatare the most important feature of schizophrenia. Anthony Grace and his co-workers have suggested, on the basis ofexperimental work using animals, that hippocampal dysfunction might produce an alteration of dopamine release inthe basal ganglia, thereby indirectly affecting the integration of information in the prefrontal cortex.[77] Others havesuggested that hippocampal dysfunction might account for disturbances in long term memory frequently observed inpeople with schizophrenia.[78]

Transient global amnesiaA current hypothesis as to one cause of transient global amnesia -- a dramatic sudden temporary near-total loss ofshort-term memory -- is that it may be due to venous congestion of the brain,[79] leading to ischemia of structuressuch as, specifically, the hippocampus that are involved with memory.[80]

EvolutionThe hippocampus has a generally similar appearance across the range of mammal species, from monotremes such asthe echidna to primates such as humans.[81] The hippocampal-size-to-body-size ratio broadly increases, being abouttwice as large for primates as for the echidna. It does not, however, increase at anywhere close to the rate of theneocortex-to-body-size ratio. Therefore, the hippocampus takes up a much larger fraction of the cortical mantle inrodents than in primates. In adult humans, the volume of the hippocampus on each side of the brain is about3–3.5 cm3, as compared to 320–420 cm3 for the volume of the neocortex.[82]

There is also a general relationship between the size of the hippocampus and spatial memory. When comparisons aremade between similar species, those that have a greater capacity for spatial memory tend to have larger hippocampalvolumes.[83] This relationship also extends to sex differences: in species where males and females show strongdifferences in spatial memory ability, they also tend to show corresponding differences in hippocampal volume.[84]

Non-mammalian species do not have a brain structure that looks like the mammalian hippocampus, but they have one that is considered homologous to it. The hippocampus, as pointed out above, is essentially the medial edge of the cortex. Only mammals have a fully developed cortex, but the structure it evolved from, called the pallium, is present in all vertebrates, even the most primitive ones such as the lamprey or hagfish.[85] The pallium is usually divided into three zones: medial, lateral, and dorsal. The medial pallium forms the precursor of the hippocampus. It does not resemble the hippocampus visually, because the layers are not warped into an S shape or enwrapped by the dentate gyrus, but the homology is indicated by strong chemical and functional affinities. There is now evidence that these

Hippocampus 11

hippocampal-like structures are involved in spatial cognition in birds, reptiles, and fish.[86]

In birds, the correspondence is sufficiently well established that most anatomists refer to the medial pallial zone asthe "avian hippocampus".[87] Numerous species of birds have strong spatial skills, particularly those that cache food.There is evidence that food-caching birds have a larger hippocampus than other types of birds, and that damage tothe hippocampus causes impairments in spatial memory.[88]

The story for fish is more complex. In teleost fish (which make up the great majority of existing species), theforebrain is distorted in comparison to other types of vertebrates: most neuroanatomists believe that the teleostforebrain is essentially everted, like a sock turned inside-out, so that structures that lie in the interior, next to theventricles, for most vertebrates, are found on the outside in teleost fish, and vice versa.[89] One of the consequencesof this is that the medial pallium ("hippocampal" zone) of a typical vertebrate is thought to correspond to the lateralpallium of a typical fish. Several types of fish (particularly goldfish) have been shown experimentally to have strongspatial memory abilities, even forming "cognitive maps" of the areas they inhabit.[83] There is evidence that damageto the lateral pallium impairs spatial memory.[90] [91]

Thus, the role of the hippocampal region in navigation appears to begin far back in vertebrate evolution, predatingsplits that occurred hundreds of millions of years ago.[92] It is not yet known whether the medial pallium plays asimilar role in even more primitive vertebrates, such as sharks and rays, or even lampreys and hagfish. Some types ofinsects, and molluscs such as the octopus, also have strong spatial learning and navigation abilities, but these appearto work differently from the mammalian spatial system, so there is as yet no good reason to think that they have acommon evolutionary origin; nor is there sufficient similarity in brain structure to enable anything resembling a"hippocampus" to be identified in these species. Some have proposed, though, that the insect's mushroom bodiesmay have a function similar to that of the hippocampus.[93]

Notes[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=164[2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Hippocampus[3] http:/ / www. neurolex. org/ wiki/ birnlex_721[4] Duvernoy, 2005[5] Gross, 1993[6] Wechsler, 2004[7] Finger, p. 183[8] cite pmid 690266[9] Eichenbaum et al., 1991[10] Vanderwolf, 2001[11] Nadel et al., 1975[12] Gray and McNaughton, 2000[13] Best & White, 1999[14] Scoville and Milner, 1957[15] N.Y. Times, 12-06-2008[16] Squire, 2009[17] Squire, 1992[18] Eichenbaum and Cohen, 1993[19] O'Keefe and Dostrovsky, 1971[20] O'Keefe and Nadel, 1978[21] Moser et al., 2008[22] Squire and Schacter, 2002[23] VanElzakker et al., 2008[24] Di Gennaro G, Grammaldo LG, Quarato PP, Esposito V, Mascia A, Sparano A, Meldolesi GN, Picardi A. Severe amnesia following

bilateral medial temporal lobe damage occurring on two distinct occasions. Neurol Sci. 2006 Jun;27(2):129–33.[25] Squire and Schacter, 2002, Ch. 1[26] Diana et al., 2007[27] Skaggs et al., 1996[28] Matsumara et al., 1999

Hippocampus 12

[29] Rolls and Xiang, 2006[30] Ekstrom et al., 2003[31] Smith and Mizumori, 2006[32] O'Keefe and Nadel[33] Chiu et al., 2004[34] Morris et al., 1982[35] Solstad et al., 2008[36] Maguire et al., 1998[37] Maguire et al., 2000[38] Amaral and Lavenex, 2006[39] Kötter & Stephan, 1997[40] Moser and Moser, 1998[41] Winson, 1978[42] Eichenbaum et al, 2007[43] Buzsáki, 2006[44] Buzsáki et al., 1990[45] Skaggs et al., 2007[46] Lubenov & Siapas, 2009[47] Buzsáki, 2002[48] Cantero et al., 2003[49] Vanderwolf, 1969[50] Huerta & Lisman, 1993[51] Kahana et al., 2001[52] Buzsáki, 1986[53] Wilson & McNaughton, 1994[54] Jackson et al., 2006[55] Sutherland & McNaughton, 2000[56] Buzsáki, 1989[57] Ramon y Cajal, 1894[58] Hebb, 1948[59] Bliss & Lømo, 1973[60] Cooke & Bliss, 2006[61] Malenka & Bear, 2004[62] Nakazawa et al., 2004[63] Hampel et al., 2008[64] Prull et al., 2000, p. 105[65] Prull et al., 2000, p. 107[66] Erickson et al., 2011[67] Rosenzweig & Barnes, 2003[68] Burke & Barnes, 2006[69] Joels, 2008[70] Fu et al, 2010[71] Campbell & MacQueen, 2004[72] Garcia-Segura, pp. 170–71[73] Chang and Lowenstein, 2003[74] Sloviter, 2005[75] Kuruba et al., 2009[76] Harrison, 2004[77] Goto & Grace, 2008[78] Boyer et al., 2007[79] Lewis, S (1998). "Aetiology of transient global amnesia". The Lancet 352: 397.[80] Chung, C. -P.; Hsu, HY; Chao, AC; Chang, FC; Sheng, WY; Hu, HH (2006). "Detection of intracranial venous reflux in patients of transient

global amnesia". Neurology 66 (12): 1873.[81] West, 1990[82] Suzuki et al, 2005[83] Jacobs, 2003[84] Jacobs et al., 1990[85] Aboitiz et al., 2003[86] Rodríguez et al., 2002

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[87] Colombo and Broadbent, 2000[88] Shettleworth, 2003[89] Nieuwenhuys, 1982[90] Portavella et al., 2002[91] Vargas et al., 2006[92] Broglio et al., 2005[93] Mizunami et al., 1998

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• West, MJ (1990). "Stereological studies of the hippocampus: a comparison of the hippocampal subdivisions ofdiverse species including hedgehogs, laboratory rodents, wild mice and men.". Prog. Brain Res. 83: 13–36.doi:10.1016/S0079-6123(08)61238-8. PMID 2203095.

• Wilson MA, McNaughton BL (1994). "Reactivation of hippocampal ensemble memories during sleep" (http:/ /www. sciencemag. org/ cgi/ pmidlookup?view=long& pmid=8036517). Science 265 (5172): 676–79.doi:10.1126/science.8036517. PMID 8036517.

• Winson J (1978). "Loss of hippocampal theta rhythm results in spatial memory deficit in the rat" (http:/ / www.sciencemag. org/ cgi/ pmidlookup?view=long& pmid=663646). Science 201 (4351): 160–63.doi:10.1126/science.663646. PMID 663646.

Hippocampus 18

Further reading

Journals• Hippocampus (http:/ / www. wiley. com/ WileyCDA/ WileyTitle/ productCd-HIPO. html) (Wiley)

Books• Per Andersen, Richard Morris, David Amaral, Tim Bliss and John O'Keefe, ed (2007). The Hippocampus Book.

Oxford University Press. ISBN 9780195100273.• Henri M. Duvernoy, F. Cattin (2005). The Human Hippocampus: Functional Anatomy, Vascularization, and

Serial Sections with MRI. Springer. ISBN 9783540231912.• Howard Eichenbaum (2002). The Cognitive Neuroscience of Memory. Oxford University Press US.

ISBN 9780195141757.• edited by Patricia E. Sharp. (2002). Patricia E. Sharp. ed. The Neural Basis of Navigation: Evidence from Single

Cell Recording. Springer. ISBN 9780792375791.• Philippe Taupin (2007). The Hippocampus: Neurotransmission and Plasticity in the Nervous System. Nova

Publishers. ISBN 9781600219146.• John H Byrne, ed (2008). Learning and Memory: A comprehensive reference. Elsevier. ISBN 9780123705099.

External links• BrainMaps at UCDavis hippocampus (http:/ / brainmaps. org/ index. php?q=hippocampus)• Diagram of a Hippocampal Brain Slice (http:/ / www. stanford. edu/ group/ maciverlab/ hippocampal. html)• Hippocampus – Cell Centered Database (http:/ / ccdb. ucsd. edu/ sand/ main?stype=lite&

keyword=hippocampus& Submit=Go& event=display& start=1)• Temporal-lobe.com An interactive diagram of the rat parahippocampal-hippocampal region (http:/ / www.

temporal-lobe. com)• NIF Search – Hippocampus (http:/ / www. neuinfo. org/ nif/ nifgwt. html?query="Hippocampus") via the

Neuroscience Information Framework• Search Hippocampus on BrainNavigator (http:/ / www. brainnav. com/ browse?highlight=8d89b5& specid=2) via

BrainNavigator

Article Sources and Contributors 19

Article Sources and ContributorsHippocampus  Source: http://en.wikipedia.org/w/index.php?oldid=412673275  Contributors: 404 page not found, 5glacieres, A More Perfect Onion, A314268, ABF, Action potential, Aitias,Alansohn, Alex.tan, Altzinn, Amaranth12498, Ancheta Wis, Andrewlp1991, Andykolandy, Angelic Wraith, Anna Lincoln, Anthonyhcole, Arcadian, Arseni, Art LaPella, Artur Lion,Autodidactyl, Avoided, AxelBoldt, Belovedfreak, BenTheMen, Benbest, Beno1000, Bhappylots, Bird, Borgx, Brain-mapper, Brockston, Bryan Derksen, Bucketoftruth, Butsuri, Cacycle,CanadianLinuxUser, Canihaveacookie, Casliber, Ccie13836, Cheekywee, Chirality, Chuunen Baka, Cit helper, Closedmouth, Cocacola456123, Colin, CommonsDelinker, CopperKettle,Cricinfouser, Crusio, D0762, Dabomb87, Dan aka jack, Dana boomer, Dando, DanielCD, Darkwind, Dave souza, Dave6, Dekimasu, Delldot, Diberri, Digfarenough, Dogerty12, DougsTech,Drmaslam, Drphilharmonic, Dtone157, Duckbill, Ealdgyth, Edward, Elbo821, Elikarag, Enirac Sum, Entilword, Epbr123, Eric Kvaalen, FG, Famousdog, Faradayplank, Farquaadhnchmn,FayssalF, Fletcherbrian, Fnielsen, Fvasconcellos, George dubya Bush, Gimme danger, Ginsengbomb, Gioto, GoodOlRickyTicky3, Gwernol, Hagerman, Hajenso, HamburgerRadio, Hdante,Health Researcher, Hekerui, Hmrox, I might be batman, Ianvitro, Invisifan, Iph, IvanLitvinov, JRGL, JWSchmidt, Jackol, James Baraldi, Jr., Japanese Searobin, Jean-Francois Gariepy, JeremyA,Jfdwolff, Jfurr1981, Jimp, Jlam4911, Jmarchn, Jmh649, Joe07734, Johnuniq, JordanITP, Jrolston, Juhachi, Kaini, Keenan ahern, Kelvinc, Kintetsubuffalo, Korpo, Kpmiyapuram, Kudret abi,Kurtle, Lars Washington, LedgendGamer, Leonard^Bloom, LittleHow, Loliveke, Looie496, Lova Falk, MBVECO, Martin451, Mbmaciver, McMannDavid, Mercury, Merlin the Wizard,Mfirbank, Mgiganteus1, Michael Devore, Michael Hardy, Michaelbusch, Mikael Häggström, Miquonranger03, Misarxist, Mrs.meganmmc, Music&Medicine, Myrvin, N.vanstrien, Najmakb,Navicular, NawlinWiki, Nbauman, Nephron, NewEnglandYankee, NifCurator1, Niteowlneils, Nrets, Odin.de, Ongar the World-Weary, Outriggr, Owen, Pacaro, Paskari, Pdmckinley, Pedant17,Peter M Gerdes, Piledhigheranddeeper, Premeditated Chaos, PsychoProf, Psychosomatic Tumor, Quietbritishjim, Rachel1, RandomP, Rbarreira, Rcarlosagis, Redpriest187, Reedy, RichFarmbrough, Riptor, Rjwilmsi, Robert Merkel, RobertG, Rreagan007, Rurigok, Ryulong, SYTYCSM, SandyGeorgia, Sasata, Sausagerooster, ScottyBerg, Sewing, Sgpsaros, Shirleybayer,SimonP, Skater11091, SpikeToronto, Spikey1973, Spiral5800, Stevenmitchell, Stuartlayton, TBHecht, Tal Celes, Tameamseo, Techdoctor, Thanhluan001, TheLimbicOne, Thuglas, Tpbradbury,Tsemii, Tucci528, UltraBibendum, Urod, Vcmartin, Vedantm, Vegetator, Was a bee, Washington irving, Wcfios, WhatamIdoing, WikiDao, Wikiwikifast, Wimt, Wingman4l7, Wouterstomp,Xenonice, 323 anonymous edits

Image Sources, Licenses and Contributorsfile:Gray739-emphasizing-hippocampus.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gray739-emphasizing-hippocampus.png  License: unknown  Contributors: User:Looie496File:Hippocampus and seahorse cropped.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Hippocampus_and_seahorse_cropped.JPG  License: Creative CommonsAttribution-Sharealike 3.0  Contributors: User:AnthonyhcoleImage:Triangle-place-cells.png  Source: http://en.wikipedia.org/w/index.php?title=File:Triangle-place-cells.png  License: Public Domain  Contributors: User:Looie496Image:Brainmaps-macaque-hippocampus.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Brainmaps-macaque-hippocampus.jpg  License: Creative Commons Attribution 3.0 Contributors: brainmaps.orgImage:CajalHippocampus (modified).png  Source: http://en.wikipedia.org/w/index.php?title=File:CajalHippocampus_(modified).png  License: Public Domain  Contributors: User:Looie496Image:Rat-hippocampal-activity-modes.png  Source: http://en.wikipedia.org/w/index.php?title=File:Rat-hippocampal-activity-modes.png  License: Public Domain  Contributors:User:Looie496

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